Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse

Abstract

In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

“…Because the quantitative relationship between FLT3 activity and clinical outcome (i.e., overall survival and objective response rate) has been establised,8, 17, 18 it is appropriate to utlilize the degree of target inhibition from early clinical trials as a surrogate marker to support dosing selection. Sorafenib and its N‐oxide metabolite showed a concentration‐dependent inhibitory effect on both FLT3 and ERK activities 9.…”

“…Numerous phase I and phase II clinical trials have been conducted to evaluate sorafenib safety and efficacy as monotherapy or in combination with traditional antileukemic chemotherapy in newly diagnosed and refractory or relapsed adult AML as well as in pediatric AML 9, 12, 13, 14, 15, 16. Overall survival benefits for the incorporation of sorafenib into combinational therapies have yet to be demonstrated, possibly due to mixed FLT3 mutations status and to a sorafenib dosing regimen that has not been optimized to balance tolerability with the achievement of 85% FLT3 inhibition, which is a predictor for clinical response 8, 17, 18. All randomized studies to date have evaluated the use of sorafenib with chemotherapy in an unselected AML population with or without FLT3 mutations at the full maximum tolerate dose (MTD) dose of 400 mg b.i.d.…”

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

“…60 Taken together, these findings suggest that FLT3 inhibitors may have better efficacy in younger patients and those with newly diagnosed disease and minimal prior chemotherapy, in whom FLT3 ligand upregulation may not be as prevalent. The Medical Research Council is currently conducting two similar studies with lestaurtinib (AML 15 and 17).…”

“…Surprisingly, in a multicenter trial of patients with relapsed AML randomized to re-induction chemotherapy alone or chemotherapy followed by lestaurtinib, the addition of lestaurtinib did not result in higher response rates or longer OS times in these patients with advanced disease. 60 A major strength of this phase 2 study is that it incorporated correlative studies in which all samples were assayed for FLT3 plasma inhibitory activity, FLT3 ligand levels and a-1 acid glycoprotein levels. The plasma inhibitory activity assay has become a standard in the field as a surrogate for determining FLT3 inhibition in patients receiving FLT3 inhibitors.…”

“…60 This may have been related to elevations in plasma FLT3 ligand and a-1 acid glycoprotein levels in response to chemotherapy. 61 Samples from patients in four separate lestaurtinib trials demonstrated that FLT3 ligand levels rise substantially after induction chemotherapy.…”